The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington's Disease Mouse Models

Vanita Chopra; Luisa Quinti; Jinho Kim; Lorraine Vollor; K. Lakshmi Narayanan; Christina Edgerly; Patricia M. Cipicchio; Molly A. Lauver; Soo Hyuk Choi; Richard B. Silverman; Robert J. Ferrante; Steven Hersch; Aleksey G. Kazantsev

doi:10.1016/j.celrep.2012.11.001

The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington's Disease Mouse Models

Vanita Chopra, Luisa Quinti, Jinho Kim, Lorraine Vollor, K. Lakshmi Narayanan, Christina Edgerly, Patricia M. Cipicchio, Molly A. Lauver, Soo Hyuk Choi, Richard B. Silverman, Robert J. Ferrante, Steven Hersch, Aleksey G. Kazantsev

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

159 Citations (Scopus)

Abstract

Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson@s disease and Huntington@s disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.

Original language	English
Pages (from-to)	1492-1497
Number of pages	6
Journal	Cell Reports
Volume	2
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2012.11.001
Publication status	Published - 2012 Dec 27

Bibliographical note

Funding Information:
This study was supported by NIH grant 1U01NS066912-01A1 to A.G.K., S.H., R.J.F., and R.B.S. A.G.K., S.H., V.C., R.J.F., and R.B.S. designed the research; V.C., L.Q., L.V., L.K., J.K., C.E., P.M.C., and S.H.C. performed research; V.C., L.Q., and R.J.F. analyzed data; and A.G.K., V.C., S.H., R.J.F., and R.B.S. wrote the paper.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2012.11.001

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title = "The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington's Disease Mouse Models",

abstract = "Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson@s disease and Huntington@s disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.",

author = "Vanita Chopra and Luisa Quinti and Jinho Kim and Lorraine Vollor and Narayanan, {K. Lakshmi} and Christina Edgerly and Cipicchio, {Patricia M.} and Lauver, {Molly A.} and Choi, {Soo Hyuk} and Silverman, {Richard B.} and Ferrante, {Robert J.} and Steven Hersch and Kazantsev, {Aleksey G.}",

note = "Funding Information: This study was supported by NIH grant 1U01NS066912-01A1 to A.G.K., S.H., R.J.F., and R.B.S. A.G.K., S.H., V.C., R.J.F., and R.B.S. designed the research; V.C., L.Q., L.V., L.K., J.K., C.E., P.M.C., and S.H.C. performed research; V.C., L.Q., and R.J.F. analyzed data; and A.G.K., V.C., S.H., R.J.F., and R.B.S. wrote the paper. ",

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AU - Chopra, Vanita

AU - Quinti, Luisa

AU - Kim, Jinho

AU - Vollor, Lorraine

AU - Narayanan, K. Lakshmi

AU - Edgerly, Christina

AU - Cipicchio, Patricia M.

AU - Lauver, Molly A.

AU - Choi, Soo Hyuk

AU - Silverman, Richard B.

AU - Ferrante, Robert J.

AU - Hersch, Steven

AU - Kazantsev, Aleksey G.

N1 - Funding Information: This study was supported by NIH grant 1U01NS066912-01A1 to A.G.K., S.H., R.J.F., and R.B.S. A.G.K., S.H., V.C., R.J.F., and R.B.S. designed the research; V.C., L.Q., L.V., L.K., J.K., C.E., P.M.C., and S.H.C. performed research; V.C., L.Q., and R.J.F. analyzed data; and A.G.K., V.C., S.H., R.J.F., and R.B.S. wrote the paper.

PY - 2012/12/27

Y1 - 2012/12/27

N2 - Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson@s disease and Huntington@s disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.

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The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington's Disease Mouse Models

Abstract

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